Prenatal Zidovudine Given to HIV-Infected Women is Safe for the Fetus
Abstract & Commentary
Synopsis: No adverse effects were observed in follow-ups of up to 5-6 years of age in HIV-uninfected children who had in utero and/or neonatal exposure to zidovudine.
Source: Culnane M, et al. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. JAMA 1999;281:151-157.
To determine possible long-term effects of in utero exposure to zidovudine (ZDV) and other retroviral drugs, Culnane and the Pediatric AIDS Clinical Trial Group studied 234 uninfected children born to 230 HIV-infected women. About half of these pregnancies were treated with ZDV antenatally and postnatally. The other half received placebo. In follow-up for 3.2-5.6 years (median, 4.2 years), there were no significant differences between treatment and placebo groups with respect to lymphocyte subsets or growth and development.
Comment by Warren A. Andiman, MD, FAAP
The remarkable and unanticipated success of the Pediatric AIDS Clinical Trials 076 study proved that it was possible to reduce by at least two-thirds the risk of vertical transmission of HIV-1 by antenatal treatment of an HIV-infected mother with ZDV.1 Soon after the results of the trial were published in 1994, administration of ZDV to an HIV-infected pregnant woman during part of the last two trimesters, during labor, and to the neonate for the first six weeks of life quickly became the regimen of choice for interrupting vertical transmission from mother to child. Thousands of women and their offspring, most living in developed countries, have been treated during the past five years. As a consequence, many babies have escaped HIV infection.
ZDV is a synthetic pyrimidine analog that has potent activity against HIV replication in vitro and in vivo. The target for this drug is the enzyme, reverse transcriptase (RT), which is essential for viral replication and is unique to retroviruses. Although the affinity of ZDV for RT is 100 times greater than its affinity for cellular DNA polymerases, clear evidence of this low-grade binding of ZDV to native DNA polymerases is evidenced by bone marrow suppression, the major clinical toxicity of the drug. Concerns about fetal damage mounted when the drug was initially given to pregnant women for the purpose of treating their infection in order to reduce their morbidity and mortality. It was felt that HIV-infected women, especially those who were symptomatic, deserved to be treated during their pregnancies and that any benefit that might accrue to the fetus in terms of preventing vertical infection would be a bonus. Still, it seemed crucial to collect evidence regarding the lack of teratogenic potential of ZDV.
The first good news regarding the virtual absence of any serious teratogenic consequences of in utero exposure to ZDV came from the original report of the results of the 076 trial, but the length of follow-up was relatively brief. Data are also available from the International Antiretroviral Pregnancy Registry (IAPR), a collaborative effort of four pharmaceutical companies involved in research and marketing of anti-HIV drugs. The registry contains all voluntary reports of prenatal exposure to seven antiretroviral agents monitored prospectively. One would expect that passive surveillance of this kind would be skewed toward reports in which an adverse outcome might be anticipated. Nevertheless, the registry findings do not show an increase in the number of birth defects associated with ZDV exposure (424 treated women were reported)—even exposure that occurred during the first trimester. Another published study that largely included participants in the Woman and Infants Transmission Study (WITS) and that comprised more than 1100 years of cumulative follow-up of enrolled children demonstrated total absence of neoplastic disease.
The current study by Culnane et al provides further reassuring data. A mean follow-up of 4.2 years among 234 uninfected children born to infected mothers who received ZDV as participants in the 076 trial revealed no adverse sequelae, including death or malignancy. Sequential data on lymphocyte subsets, growth parameter Z-scores, and cognitive/developmental function failed to identify differences between children exposed to ZDV in utero and postpartum and those exposed to placebo.
Despite this growing number of encouraging reports, two challenges remain for the future: 1) a continuing need to follow increasing numbers of pregnant women who are being placed on a wide variety of therapeutic and preventive regimens; and 2) the need to ensure the availability of systems to provide long-term follow-up of drug-exposed babies. Many pregnant women are currently being placed on multidrug regimens of highly active antiretroviral drugs, only a few of which have completed testing in long-term animal carcinogenicity studies. Information regarding placental passage of these drugs or newborn-to-mother drug ratios has not been collected for at least half of these agents. There is likely to be a dramatic expansion in the number of fetuses who will be exposed to ZVD and other antiretrovirals, if only briefly. It will be increasingly difficult to follow large numbers of these babies for prolonged periods. Only continued vigilance on the part of clinical investigators and caregivers can ensure that follow-up will occur at least through the early childbearing years of children exposed in utero. (Dr. Andiman is Professor of Pediatrics and Director of the Pediatric HIV/AIDS program at the Yale-New Haven Children’s Hospital.)
Reference
1. Connor EM, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-1180.
Prenatal treatment of HIV-infected pregnant women with zidovudine:
a. is teratogenic.
b. reduces the frequency of vertical transmission of HIV by approximately one-third.
c. is associated with decreases in long-term growth and development.
d. is not associated with a recognized risk of malignancy in the child.
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